We have begun a program of research to develop a laboratory model of cocaine abuse using very low doses of oral cocaine, doses that produce measurable behavioral effects but minimal cardiovascular effects. The first protocol in this research program used a drug discrimination procedure to explore the limits of human behavioral sensitivity to oral cocaine. Initially, subjects in this protocol are taught to distinguish 50 mg of oral cocaine from placebo using a drug discrimination procedure. Then subjects were exposed to 4 doses of oral cocaine (6.25 mg, 12.5 mg, 25 mg, and 50 mg) and placebo in random order across days to determine the lowest doses of cocaine that subjects can detect. A second study was initiated to identify the lowest dose of oral cocaine that subjects could detect by first teaching subjects to distinguish 50 mg of oral cocaine from placebo and then gradually decreasing the dose of oral cocaine while continuing discrimination training. Throughout both studies the cardiovascular and self-reported mood effects of these cocaine doses were determined. These studies demonstrated behavioral activity of doses of oral cocaine that are lower than those previously shown to affect human behavior. Oral cocaine produced a similar profile of self-reported mood and performance effects as cocaine administered by other routes. These methods revealed important behavioral effects of oral cocaine at doses that produced minimal or no detectable cardiovascular effects. The results of this study suggest that these procedures may be useful in studying the behavioral pharmacology of cocaine under conditions that minimize risk to subjects. Further studies are planned to study cocaine and opioid drug discrimination, cocaine and opioid self-administration studies, and a multiple-choice behavioral paradigm for screen medications.